Obstructive sleep apnea (OSA) is a common sleep disorder that can cause cognitive impairment (CI). Physical interventions, such as continuous positive airway pressure, may help to prevent OSA, but the discomfort of wearing such a device during sleep hinders its practical use. This limitation highlights the clinical importance of pharmaceutical interventions that can prevent OSA or its major sequelae. In this study, we will test and validate animal models that are susceptible to OSA-triggered CI and will determine the efficacy of a novel compound in preventing this CI in a relevant mouse model. OSA does not cause CI in every patient; rather, it occurs in only one-quarter of the susceptible patients. Although it is unclear what may lead to the development of this subgroup of patients susceptible to CI, we recently discovered that G protein-coupled receptor kinase-5 (GRK5) deficiency does so in mice. In fact, GRK5 deficiency makes the subjects susceptible to CI that is triggered not only by chronic intermittent hypoxia (CIH) or OSA but also by mutant human ?-amyloid (A?) precursor protein (APP) and aging. The underlying mechanisms are a series of cascading events that all begin with a selectively impaired M2 muscarinic receptor desensitization that is caused by the loss or deficiency of GRK5. Omitting much of the detail, the high selectivity on M2 receptors limits the entire impact on the cholinergic system, which includes not only the basal forebrain (BF) cholinergic neurons but also the postsynaptic cholinoceptive neurons that are widely distributed in the hippocampus as well. The actual impact of GRK5 deficiency on the cholinergic system is to rather inconspicuously make the cholinergic and cholinoceptive neurons vulnerable, which invites secondary degenerative insults such as A? or CIH to trigger neurodegeneration. Owing to the high selectivity of GRK5 deficiency on M2 receptors, a selective M2 blockade was found to be highly effective in preventing the cascading events. In this regard, CN158 is a novel M2 selective antagonist (patent pending) that outperforms other known M2 antagonists. Moreover, it had outstanding pharmacological properties in our preliminary in vivo studies and therefore will be tested in this project. We hypothesize that CIH-triggered CI is more likely to occur in GRK5-deficient subjects and that an M2 blockade by CN158 can effectively prevent CIH-triggered CI and the underlying neurodegeneration in the BF cholinergic and hippocampal cholinoceptive neurons in GRK5-deficient mice. We will address our hypothesis through the following Specific Aims: Aim 1. To verify whether GRK5 deficiency leads to susceptibility to CIH-triggered CI and the underlying neurodegeneration of the cholinergic system, we will expose GRK5-deficient mice to various CIH conditions before assessing their behavioral and neuropathological changes. Aim 2. To determine whether M2 blockade by CN158 effectively prevents CIH-triggered CI and the degeneration of the cholinergic system, we will treat GRK5-deficient mice exposed to an optimal CIH condition with CN158 and a known M2 antagonist control (anthranilamide derivative 23) in a randomized trial with the same behavioral and neuropathological analyses used in Aim 1. The success of this project is expected to establish empirical evidence that CIH-triggered CI in GRK5-deficient subjects is pharmaceutically preventable and that CN158 may serve as a lead compound in fulfilling such a purpose.